Radiopharmceutical complexes targeting prostate-specific membrane antigen and its combinations

Abstract

The present invention relates to tissue-targeting compounds. In particular, the present invention relates to tissue-targeting compounds comprising a monoclonal antibody or an antigen-binding fragment thereof having binding affinity for the prostate-specific membrane antigen (PSMA). Further, the present invention relates to combinations, preferably pharmaceutical combinations comprising a tissue-targeting compound of formula (I) and a further pharmaceutical agent. Said combinations are useful in therapy, preferably in treating hyperproliferative diseases such as cancer.

1 . A tissue-targeting compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein [Ab] is a monoclonal antibody or an antigen-binding fragment thereof having binding affinity for a prostate-specific membrane antigen (PSMA). 
       
     
     
         2 . The tissue-targeting compound of formula (I) according to  claim 1 , wherein [Ab] is Pelgifatamab or an antigen-binding fragment thereof, J591 or an antigen-binding fragment thereof, or TLX592 or an antigen-binding fragment thereof. 
     
     
         3 . The tissue-targeting compound of formula (I) according to  claim 1 , wherein [Ab] is Pelgifatamab or an antigen-binding fragment thereof. 
     
     
         4 . The tissue-targeting compound of formula (I) according to  claim 1 , wherein [Ab] is Pelgifatamab or an antigen-binding fragment thereof comprising at least three CDR heavy chain sequences according to SEQ ID NO. 5, SEQ ID NO. 6 and SEQ ID NO. 7 and three CDR light chain sequences according to SEQ ID NO. 8, SEQ ID NO. 9 and SEQ ID NO. 10. 
     
     
         5 . The tissue-targeting compound of formula (I) according to  claim 1 , wherein [Ab] is J591 or an antigen-binding fragment thereof comprising at least three CDR heavy chain sequences according to SEQ ID NO. 13, SEQ ID NO. 14 and SEQ ID NO. 15 and three CDR light chain sequences according to SEQ ID NO. 16, SEQ ID NO. 17 and SEQ ID NO. 18. 
     
     
         6 . The tissue-targeting compound of formula (I) according to  claim 1 , wherein [Ab] is TLX592 or an antigen-binding fragment thereof comprising at least three CDR heavy chain sequences according to SEQ ID NO. 21, SEQ ID NO. 22 and SEQ ID NO. 23 and three CDR light chain sequences according to SEQ ID NO. 24, SEQ ID NO. 25 and SEQ ID NO. 26. 
     
     
         7 . A process for the preparation of a tissue-targeting compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein [Ab] is a monoclonal antibody or an antigen-binding fragment thereof having binding affinity for PSMA, 
         said method comprising
 (i) coupling a chelating moiety of formula (II) 
 
       
       
         
           
           
               
               
           
         
         with a monoclonal antibody or an antigen-binding fragment thereof having binding affinity for PSMA to form a product, and
 (ii) contacting the product with an aqueous solution comprising an ion of at least one alpha-emitting actinium isotope. 
 
       
     
     
         8 . The process according to  claim 7 , wherein [Ab] is Pelgifatamab or an antigen-binding fragment thereof,
 said method comprising
 (i) coupling a chelating moiety of formula (II) 
   
       
         
           
           
               
               
           
         
         with Pelgifatamab or an antigen-binding fragment thereof via a Lysine residue of the monoclonal antibody or antigen-binding fragment thereof to form a product, and
 (ii) contacting the product with an aqueous solution comprising an ion of at least one alpha-emitting actinium isotope. 
 
       
     
     
         9 . The process according to  claim 7 , wherein [Ab] is Pelgifatamab or an antigen-binding fragment thereof,
 said method comprising   (i) coupling a chelating moiety of formula (II)   
       
         
           
           
               
               
           
         
       
       with Pelgifatamab or an antigen-binding fragment thereof via a Lysine residue of the monoclonal antibody or antigen-binding fragment thereof to form a product, and
 (ii) contacting the product with an aqueous solution comprising an ion of at least one alpha-emitting actinium isotope, 
 
       wherein Pelgifatamab or an antigen-binding fragment thereof comprises at least three CDR heavy chain sequences according to SEQ ID NO. 5, SEQ ID NO. 6 and SEQ ID NO. 7 and three CDR light chain sequences according to SEQ ID NO. 8, SEQ ID NO. 9 and SEQ ID NO. 10. 
     
     
         10 . A tissue-targeting chelator of formula (III) 
       
         
           
           
               
               
           
         
       
       wherein [Ab] is a monoclonal antibody or an antigen-binding fragment thereof having binding affinity for PSMA. 
     
     
         11 . The tissue-targeting chelator of formula (III) according to  claim 10 , wherein [Ab] is Pelgifatamab or an antigen-binding fragment thereof, J591 or an antigen-binding fragment thereof, or TLX592 or an antigen-binding fragment thereof. 
     
     
         12 . The tissue-targeting chelator of formula (III) according to  claim 10 , wherein [Ab] is Pelgifatamab or an antigen-binding fragment thereof. 
     
     
         13 . The tissue-targeting chelator of formula (III) according to  claim 10 , wherein [Ab] is Pelgifatamab or an antigen-binding fragment thereof comprising at least, three CDR heavy chain sequences according to SEQ ID NO. 5, SEQ ID NO. 6 and SEQ ID NO. 7 and three CDR light chain sequences according to SEQ ID NO. 8, SEQ ID NO. 9 and SEQ ID NO. 10. 
     
     
         14 . The tissue-targeting chelator of formula (III) according to  claim 10 , wherein [Ab] is J591 or an antigen-binding fragment thereof comprising at least three CDR heavy chain sequences according to SEQ ID NO. 13, SEQ ID NO. 14 and SEQ ID NO. 15 and three CDR light chain sequences according to SEQ ID NO. 16, SEQ ID NO. 17 and SEQ ID NO. 18. 
     
     
         15 . The tissue-targeting chelator of formula (III) according to  claim 10 , wherein [Ab] is TLX592 or an antigen-binding fragment thereof comprising at least three CDR heavy chain sequences according to SEQ ID NO. 21, SEQ ID NO. 22 and SEQ ID NO. 23 and three CDR light chain sequences according to SEQ ID NO. 24, SEQ ID NO. 25 and SEQ ID NO. 26. 
     
     
         16 . A use of a tissue-targeting chelator of formula (III) according to  claim 10  for preparation of a tissue-targeting compound of formula (I) according to  claim 1 . 
     
     
         17 . A combination comprising
 (i) a tissue-targeting compound of formula (I)   
       
         
           
           
               
               
           
         
         
           wherein [Ab] is a monoclonal antibody or an antigen-binding fragment thereof having binding affinity for a prostate-specific membrane antigen (PSMA), and 
         
         (ii) a pharmaceutical agent selected from a non-steroidal antiandrogen, a steroidal antiandrogen, an androgen synthesis inhibitor, an antigonadotropin, a PARP inhibitor, an ATR inhibitor, an ATM inhibitor, a DNA-PK inhibitor, an AKT inhibitor, a Pi3K inhibitor, a PSMA-targeting beta emitter, an immune checkpoint inhibitor, an alpha emitter, a vaccine and a chemotherapeutic agent. 
       
     
     
         18 . The combination according to  claim 17 , wherein [Ab] is Pelgifatamab or an antigen-binding fragment thereof comprising at least three CDR heavy chain sequences according to SEQ ID NO. 5, SEQ ID NO. 6 and SEQ ID NO. 7 and three CDR light chain sequences according to SEQ ID NO. 8, SEQ ID NO. 9 and SEQ ID NO. 10. 
     
     
         19 . The combination according to  claim 17 , wherein the pharmaceutical agent is selected from a non-steroidal antiandrogen, a steroidal antiandrogen, an androgen synthesis inhibitor, an antigonadotropin, a PARP inhibitor, a PSMA-targeting beta emitter, an alpha emitter, a vaccine and a chemotherapeutic agent. 
     
     
         20 . The combination according to  claim 17 , wherein the pharmaceutical agent is selected from a non-steroidal antiandrogen, a steroidal antiandrogen, an androgen synthesis inhibitor, and an antigonadotropin. 
     
     
         21 . The combination according to  claim 17 , wherein the pharmaceutical agent is selected from a non-steroidal antiandrogen selected from the group consisting of darolutamide, bicalutamide, enzalutamide, apalutamide, flutamide, nilutamide and topilutamide, a steroidal antiandrogen selected from the group consisting of Cyproterone acetate, Allylestrenol, Chlormadinone acetate, Delmadinone acetate, Gestonorone caproate, Hydroxyprogesterone caproate, Medroxyprogesterone acetate, Megestrol acetate, Osaterone acetate, Oxendolone and Spironolactone, an androgen synthesis inhibitor selected from the group consisting of ketoconazole, abiraterone, aminoglutethimide, goserelin and seviteronel, an antigonadotropin selected from the group consisting of Abarelix, Danazol, Gestrinone, Paroxypropione, Cetrorelix, Degarelix, Elagolix, Ganirelix, Linzagolix and Relugolix and a PARP inhibitor selected from the group consisting of Olaparib, Rucaparib, Veliparib, Niraparib, Talazoparib, Pamiparib, CEP 9722, E7016 and Iniparib. 
     
     
         22 . The combination according to  claim 17 , wherein the pharmaceutical agent is selected from a non-steroidal antiandrogen selected from the group consisting of darolutamide, bicalutamide, enzalutamide, apalutamide, flutamide, nilutamide and topilutamide, a steroidal antiandrogen selected from the group consisting of Cyproterone acetate, Allylestrenol, Chlormadinone acetate, Delmadinone acetate, Gestonorone caproate, Hydroxyprogesterone caproate, Medroxyprogesterone acetate, Megestrol acetate, Osaterone acetate, Oxendolone and Spironolactone, an androgen synthesis inhibitor selected from the group consisting of ketoconazole, abiraterone, aminoglutethimide, goserelin and seviteronel and an antigonadotropin selected from the group consisting of Abarelix, Danazol, Gestrinone, Paroxypropione, Cetrorelix, Degarelix, Elagolix, Ganirelix, Linzagolix and Relugolix. 
     
     
         23 . The combination according to  claim 17 , wherein the pharmaceutical agent is selected from the group consisting of darolutamide, Cyproterone acetate, abiraterone or goserelin and Degarelix or Relugolix. 
     
     
         24 . The combination according to  claim 17 , wherein the pharmaceutical agent is darolutamide. 
     
     
         25 . A method of treating a disease comprising the step of administering a tissue-targeting compound of formula (I) according to  claim 1  in a therapeutically effective amount to a patient in need thereof any of  claims 1 to 6  or a combination according to any of  claims 17 to 24  for use in the treatment of disease. 
     
     
         26 . The method of  claim 25 , wherein the disease is characterized by an overexpression of prostate-specific membrane antigen (PSMA). 
     
     
         27 . The method of  claim 25 , wherein the disease is cancer, further wherein the cancer is prostate cancer. 
     
     
         28 . A method for the treatment of a disease, comprising the step of administering the compound of formula (I) according to  claim 1  in a therapeutically effective amount to a patient in need thereof, wherein the disease is a hyperproliferative disease, further wherein the hyperproliferative disease is cancer. 
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . A method of treatment of disease, wherein the disease is a hyperproliferative disease, further wherein the hyperproliferative disease is cancer comprising administering to said subject a therapeutically effective amount of a tissue-targeting compound of formula (I) according to  claim 1 . 
     
     
         32 . The method according to  claim 25 , wherein the disease is prostate cancer. 
     
     
         33 . A composition containing a combination according to  claim 17  further comprising pharmaceutically acceptable ingredients. 
     
     
         34 . A kit comprising a combination of
 a tissue-targeting compound of formula (I) according to  claim 1  and a pharmaceutical agent;   and, optionally, one or more further pharmaceutical agents;   in which optionally both or either one of the tissue-targeting compound of formula (I) or the pharmaceutical agent are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.